tbuckley/cabot-search huggingface dataset:
Multiomic profiling of cutaneous leishmaniasis infections reveals microbiota-driven mechanisms underlying disease severity
Authors: Camila Farias Amorim, Victoria M. Lovins, Tej Pratap Singh, Fernanda O. Novais, Jordan C. Harris, Alexsandro S. Lago, Lucas P. Carvalho, Edgar M. Carvalho, Daniel P. Beiting, Phillip Scott, Elizabeth A. Grice
Journal: Science Translational Medicine (2023)

Leishmania braziliensis is a parasitic infection that can result in inflammation and skin injury with highly variable and unpredictable clinical outcomes. Here, we investigated the potential impact of microbiota on infection-induced inflammatory responses and disease resolution by conducting an integrated analysis of the skin microbiome and host transcriptome on a cohort of 62 patients infected with L. braziliensis . We found that overall bacterial burden and microbiome configurations dominated with Staphylococcus spp. were associated with delayed healing and enhanced inflammatory responses, especially by IL-1 family members. Quantification of host and bacterial transcripts on human lesions revealed that high lesional S. aureus transcript abundance was associated with delayed healing and increased expression of IL-1β. This cytokine was critical for modulating disease outcomes in L. braziliensis –infected mice colonized with S. aureus , given that its neutralization reduced pathology and inflammation. These results highlight how the human microbiome can shape disease outcomes in cutaneous leishmaniasis and suggest pathways toward host-directed therapies to mitigate the inflammatory consequences.
Microsimulation as a flexible tool to evaluate policies and their impact on socioeconomic inequalities in health
Authors: Daniel Kopasker, Srinivasa Vittal Katikireddi, João Vasco Santos, Matteo Richiardi, Patryk Bronka, Mikael Rostila, Michele Cecchini, Shehzad Ali, Karl Emmert-Fees, Clare Bambra, Hanno Hoven, Insa Backhaus, Mirza Balaj, Terje Andreas Eikemo
Journal: The Lancet Regional Health - Europe (2023)
Sexual and reproductive healthcare must be disability inclusive
Authors: Joy Shu’aibu
Journal: BMJ (2023)

Sexual and reproductive healthcare must be disability inclusive With women's rights being rolled back across the world, it is more important than ever for sexual health and family planning services to be disability inclusive, says Joy Shu'aibu Joy Shu'aibu director of programme operations in NigeriaIn May this year, G7 leaders made an unusually political statement denouncing the "well coordinated and funded rollback on gender and rights movements at country and multilateral levels."
Teplizumab and β-Cell Function in Newly Diagnosed Type 1 Diabetes
Authors: Eleanor L. Ramos, Colin M. Dayan, Lucienne Chatenoud, Zdenek Sumnik, Kimber M. Simmons, Agnieszka Szypowska, Stephen E. Gitelman, Laura A. Knecht, Elisabeth Niemoeller, Wei Tian, Kevan C. Herold
Journal: New England Journal of Medicine (2023)

Teplizumab, a humanized monoclonal antibody to CD3 on T cells, is approved by the Food and Drug Administration to delay the onset of clinical type 1 diabetes (stage 3) in patients 8 years of age or older with preclinical (stage 2) disease. Whether treatment with intravenous teplizumab in patients with newly diagnosed type 1 diabetes can prevent disease progression is unknown. In this phase 3, randomized, placebo-controlled trial, we assessed β-cell preservation, clinical end points, and safety in children and adolescents who were assigned to receive teplizumab or placebo for two 12-day courses. The primary end point was the change from baseline in β-cell function, as measured by stimulated C-peptide levels at week 78. The key secondary end points were the insulin doses that were required to meet glycemic goals, glycated hemoglobin levels, time in the target glucose range, and clinically important hypoglycemic events. Patients treated with teplizumab (217 patients) had significantly higher stimulated C-peptide levels than patients receiving placebo (111 patients) at week 78 (least-squares mean difference, 0.13 pmol per milliliter; 95% confidence interval [CI], 0.09 to 0.17; P<0.001), and 94.9% (95% CI, 89.5 to 97.6) of patients treated with teplizumab maintained a clinically meaningful peak C-peptide level of 0.2 pmol per milliliter or greater, as compared with 79.2% (95% CI, 67.7 to 87.4) of those receiving placebo. The groups did not differ significantly with regard to the key secondary end points. Adverse events occurred primarily in association with administration of teplizumab or placebo and included headache, gastrointestinal symptoms, rash, lymphopenia, and mild cytokine release syndrome. Two 12-day courses of teplizumab in children and adolescents with newly diagnosed type 1 diabetes showed benefit with respect to the primary end point of preservation of β-cell function, but no significant differences between the groups were observed with respect to the secondary end points. (Funded by Provention Bio and Sanofi; PROTECT ClinicalTrials.gov number, NCT03875729.)
Elucidating regulatory processes of intense physical activity by multi-omics analysis
Authors: Ernesto S. Nakayasu, Marina A. Gritsenko, Young-Mo Kim, Jennifer E. Kyle, Kelly G. Stratton, Carrie D. Nicora, Nathalie Munoz, Kathleen M. Navarro, Daniel Claborne, Yuqian Gao, Karl K. Weitz, Vanessa L. Paurus, Kent J. Bloodsworth, Kelsey A. Allen, Lisa M. Bramer, Fernando Montes, Kathleen A. Clark, Grant Tietje, Justin Teeguarden, Kristin E. Burnum-Johnson
Journal: Military Medical Research (2023)

Abstract Background Physiological and biochemical processes across tissues of the body are regulated in response to the high demands of intense physical activity in several occupations, such as firefighting, law enforcement, military, and sports. A better understanding of such processes can ultimately help improve human performance and prevent illnesses in the work environment. Methods To study regulatory processes in intense physical activity simulating real-life conditions, we performed a multi-omics analysis of three biofluids (blood plasma, urine, and saliva) collected from 11 wildland firefighters before and after a 45 min, intense exercise regimen. Omics profiles post- versus pre-exercise were compared by Student’s t -test followed by pathway analysis and comparison between the different omics modalities. Results Our multi-omics analysis identified and quantified 3835 proteins, 730 lipids and 182 metabolites combining the 3 different types of samples. The blood plasma analysis revealed signatures of tissue damage and acute repair response accompanied by enhanced carbon metabolism to meet energy demands. The urine analysis showed a strong, concomitant regulation of 6 out of 8 identified proteins from the renin-angiotensin system supporting increased excretion of catabolites, reabsorption of nutrients and maintenance of fluid balance. In saliva, we observed a decrease in 3 pro-inflammatory cytokines and an increase in 8 antimicrobial peptides. A systematic literature review identified 6 papers that support an altered susceptibility to respiratory infection. Conclusion This study shows simultaneous regulatory signatures in biofluids indicative of homeostatic maintenance during intense physical activity with possible effects on increased infection susceptibility, suggesting that caution against respiratory diseases could benefit workers on highly physical demanding jobs.
Trends and Outcomes of Assisted Reproductive Technology Cycles Using a Gestational Carrier Between 2014 and 2020
Authors: Lisa M. Shandley, Carol E. DeSantis, Jacqueline C. Lee, Jennifer F. Kawwass, Heather S. Hipp
Journal: JAMA (2023)

This study used national surveillance data from the Society for Assisted Reproductive Technology to describe trends and outcomes in assisted reproductive technology cycles using a gestational carrier vs those not using a gestational carrier.
Mind the GAP: RASA2 and RASA3 GTPase-activating proteins as gatekeepers of T cell activation and adhesion
Authors: Kristoffer H. Johansen, Dominic P. Golec, Klaus Okkenhaug, Pamela L. Schwartzberg
Journal: Trends in Immunology (2023)

Following stimulation, the T cell receptor (TCR) and its coreceptors integrate multiple intracellular signals to initiate T cell proliferation, migration, gene expression, and metabolism. Among these signaling molecules are the small GTPases RAS and RAP1, which induce MAPK pathways and cellular adhesion to activate downstream effector functions. Although many studies have helped to elucidate the signaling intermediates that mediate T cell activation, the molecules and pathways that keep naive T cells in check are less understood. Several recent studies provide evidence that RASA2 and RASA3, which are GAP1-family GTPase-activating proteins (GAPs) that inactivate RAS and RAP1, respectively, are crucial molecules that limit T cell activation and adhesion. In this review we describe recent data on the roles of RASA2 and RASA3 as gatekeepers of T cell activation and migration.
Tet1 deficiency exacerbates oxidative stress in acute kidney injury by regulating superoxide dismutase
Authors: Yu Fan, Yangmian Yuan, Mingrui Xiong, Muchuan Jin, Donge Zhang, Dong Yang, Chengyu Liu, Robert B. Petersen, Kun Huang, Anlin Peng, Ling Zheng
Journal: Theranostics (2023)

Rationale: Increased methylation of key genes has been observed in kidney diseases, suggesting that the ten-eleven translocation (Tet) methyl-cytosine dioxygenase family as well as 5mC oxidation may play important roles. As a member of the Tet family, the role of Tet1 in acute kidney injury (AKI) remains unclear. Methods:Tet1 knockout mice, with or without tempol treatment, a scavenger of reactive oxygen species (ROS), were challenged with ischemia and reperfusion (I/R) injury or unilateral ureteral obstruction (UUO) injury. RNA-sequencing, Western blotting, qRT-PCR, bisulfite sequencing, chromatin immunoprecipitation, immunohistochemical staining, and dot blot assays were performed. Results: Tet1 expression was rapidly upregulated following I/R or UUO injury. Moreover, Tet1 knockout mice showed increased renal injury and renal cell death, increased ROS accumulation, G2/M cell cycle arrest, inflammation, and fibrosis. Severe renal damage in injured Tet1 knockout mice was alleviated by tempol treatment. Mechanistically, Tet1 reduced the 5mC levels in an enzymatic activity-dependent manner on the promoters of Sod1 and Sod2 to promote their expression, thus lowering injury-induced excessive ROS and reducing I/R or UUO injury. Conclusions: Tet1 plays an important role in the development of AKI by promoting SOD expression through a DNA demethylase-dependent mechanism.
Stimuli-activatable nanomedicine meets cancer theranostics
Authors: Haonan Li, Yue Feng, Qiang Luo, Zhiqian Li, Xue Li, Huatian Gan, Zhongwei Gu, Qiyong Gong, Kui Luo
Journal: Theranostics (2023)

Stimuli-activatable strategies prevail in the design of nanomedicine for cancer theranostics.Upon exposure to endogenous/exogenous stimuli, the stimuli-activatable nanomedicine could be self-assembled, disassembled, or functionally activated to improve its biosafety and diagnostic/therapeutic potency.A myriad of tumor-specific features, including a low pH, a high redox level, and overexpressed enzymes, along with exogenous physical stimulation sources (light, ultrasound, magnet, and radiation) have been considered for the design of stimuli-activatable nano-medicinal products.Recently, novel stimuli sources have been explored and elegant designs emerged for stimuli-activatable nanomedicine.In addition, multi-functional theranostic nanomedicine has been employed for imaging-guided or image-assisted antitumor therapy.In this review, we rationalize the development of theranostic nanomedicine for clinical pressing needs.Stimuli-activatable self-assembly, disassembly or functional activation approaches for developing theranostic nanomedicine to realize a better diagnostic/therapeutic efficacy are elaborated and state-of-the-art advances in their structural designs are detailed.A reflection, clinical status, and future perspectives in the stimuli-activatable nanomedicine are provided.
Dual-response of multi-functional microsphere system to ultrasound and microenvironment for enhanced bone defect treatment
Authors: Qingxu Song, Dianwei Wang, Haoyu Li, Zongliang Wang, Songjia Sun, Zhenyu Wang, Yi Liu, Sien Lin, Gang Li, Shaokun Zhang, Peibiao Zhang
Journal: Bioactive Materials (2023)

Using bone tissue engineering strategies to achieve bone defect repair is a promising modality. However, the repair process outcomes are often unsatisfactory. Here we properly designed a multi-functional microsphere system, which could deliver bioactive proteins under the dual response of ultrasound and microenvironment, release microenvironment-responsive products on demand, reverse bone injury microenvironment, regulate the immune microenvironment, and achieve excellent bone defect treatment outcomes. In particular, the MnO2 introduced into the poly(lactic-co-glycolic acid) (PLGA) microspheres during synthesis could consume the acid produced by the degradation of PLGA to protect bone morphogenetic protein-2 (BMP-2). More importantly, MnO2 could consume reactive oxygen species (ROS) and produce Mn2+ and oxygen (O2), further promoting the repair of bone defects while reversing the microenvironment. Moreover, the reversal of the bone injury microenvironment and the depletion of ROS promoted the polarization of M1 macrophages to M2 macrophages, and the immune microenvironment was regulated. Notably, the ultrasound (US) irradiation used during treatment also allowed the on-demand release of microenvironment-responsive products. The multi-functional microsphere system combines the effects of on-demand delivery, reversal of bone injury microenvironment, and regulation of the immune microenvironment, providing new horizons for the clinical application of protein delivery and bone defect repair.
Rosuvastatin versus atorvastatin treatment in adults with coronary artery disease: secondary analysis of the randomised LODESTAR trial
Authors: Yong-Joon Lee, Sung-Jin Hong, Woong Chol Kang, Bum-Kee Hong, Jong-Young Lee, Jin-Bae Lee, Hyung-Jin Cho, Junghan Yoon, Seung-Jun Lee, Chul-Min Ahn, Jung-Sun Kim, Byeong-Keuk Kim, Young-Guk Ko, Donghoon Choi, Yangsoo Jang, Myeong-Ki Hong
Journal: BMJ (2023)

To compare the long term efficacy and safety of rosuvastatin with atorvastatin treatment in adults with coronary artery disease.Randomised, open label, multicentre trial.12 hospitals in South Korea, September 2016 to November 2019.4400 adults (age ≥19 years) with coronary artery disease.Participants were assigned to receive either rosuvastatin (n=2204) or atorvastatin (n=2196) using 2×2 factorial randomisation.The primary outcome was a three year composite of all cause death, myocardial infarction, stroke, or any coronary revascularisation. Secondary outcomes were safety endpoints: new onset diabetes mellitus; hospital admissions due to heart failure; deep vein thrombosis or pulmonary thromboembolism; endovascular revascularisation for peripheral artery disease; aortic intervention or surgery; end stage kidney disease; discontinuation of study drugs owing to intolerance; cataract surgery; and a composite of laboratory detected abnormalities.4341 of the 4400 participants (98.7%) completed the trial. Mean daily dose of study drugs was 17.1 mg (standard deviation (SD) 5.2 mg) in the rosuvastatin group and 36.0 (12.8) mg in the atorvastatin group at three years (P<0.001). The primary outcome occurred in 189 participants (8.7%) in the rosuvastatin group and 178 (8.2%) in the atorvastatin group (hazard ratio 1.06, 95% confidence interval 0.86 to 1.30; P=0.58). The mean low density lipoprotein (LDL) cholesterol level during treatment was 1.8 mmol/L (SD 0.5 mmol/L) in the rosuvastatin group and 1.9 (0.5) mmol/L in the atorvastatin group (P<0.001). The rosuvastatin group had a higher incidence of new onset diabetes mellitus requiring initiation of antidiabetics (7.2% v 5.3%; hazard ratio 1.39, 95% confidence interval 1.03 to 1.87; P=0.03) and cataract surgery (2.5% v 1.5%; 1.66, 1.07 to 2.58; P=0.02). Other safety endpoints did not differ between the two groups.In adults with coronary artery disease, rosuvastatin and atorvastatin showed comparable efficacy for the composite outcome of all cause death, myocardial infarction, stroke, or any coronary revascularisation at three years. Rosuvastatin was associated with lower LDL cholesterol levels but a higher risk of new onset diabetes mellitus requiring antidiabetics and cataract surgery compared with atorvastatin.ClinicalTrials.gov NCT02579499.
Clinical effectiveness of septoplasty versus medical management for nasal airways obstruction: multicentre, open label, randomised controlled trial
Authors: Sean Carrie, James O’Hara, Tony Fouweather, Tara Homer, Nikki Rousseau, Leila Rooshenas, Alison Bray, Deborah D Stocken, Laura Ternent, Katherine Rennie, Emma Clark, Nichola Waugh, Alison J Steel, Jemima Dooley, Michael Drinnan, David Hamilton, Kelly Lloyd, Yemi Oluboyede, Caroline Wilson, Quentin Gardiner, Naveed Kara, Sadie Khwaja, Samuel C Leong, Sangeeta Maini, Jillian Morrison, Paul Nix, Janet A Wilson, M Dawn Teare
Journal: BMJ (2023)

To assess the clinical effectiveness of septoplasty.Multicentre, randomised controlled trial.17 otolaryngology clinics in the UK's National Health Service.378 adults (≥18 years, 67% men) newly referred with symptoms of nasal obstruction associated with septal deviation and at least moderate symptoms of nasal obstruction (score >30 on the Nasal Obstruction and Symptom Evaluation (NOSE) scale).Participants were randomised 1:1 to receive either septoplasty (n=188) or defined medical management (n=190, nasal steroid and saline spray for six months), stratified by baseline symptom severity and sex.The primary outcome measure was patient reported score on the Sino-Nasal Outcome Test-22 (SNOT-22) at six months, with 9 points defined as the minimal clinically important difference. Secondary outcomes included quality of life and objective nasal airflow measures.Mean SNOT-22 scores at six months were 19.9 (95% confidence interval 17.0 to 22.7) in the septoplasty arm (n=152, intention-to-treat population) and 39.5 (36.1 to 42.9) in the medical management arm (n=155); an estimated 20.0 points lower (better) for participants randomised to receive septoplasty (95% confidence interval 16.4 to 23.6, P<0.001, adjusted for baseline continuous SNOT-22 score and the stratification variables sex and baseline NOSE severity categories). Greater improvement in SNOT-22 scores was predicted by higher baseline symptom severity scores. Quality of life outcomes and nasal airflow measures (including peak nasal inspiratory flow and absolute inhalational nasal partitioning ratio) improved more in participants in the septoplasty group. Readmission to hospital with bleeding after septoplasty occurred in seven participants (4% of 174 who had septoplasty), and a further 20 participants (12%) required antibiotics for infections.Septoplasty is a more effective intervention than a defined medical management regimen with a nasal steroid and saline spray in adults with nasal obstruction associated with a deviated nasal septum.ISRCTN Registry ISRCTN16168569.
Biomimetic Nanocarriers of Pro‐Resolving Lipid Mediators for Resolution of Inflammation in Atherosclerosis
Authors: Maria Anghelache, Geanina Voicu, Mariana Deleanu, Mihaela Turtoi, Florentina Safciuc, Ruxandra Anton, Delia Boteanu, Ioana Madalina Fenyo, Ileana Manduteanu, Maya Simionescu, Manuela Calin
Journal: Advanced Healthcare Materials (2023)

Abstract Atherosclerosis (ATH) is a systemic disease characterized by a chronic inflammatory process and lipid deposition in the arterial walls. The chronic inflammation within ATH lesions results, at least in part, from the failed resolution of inflammation. This process is controlled actively by specialized pro‐resolving lipid mediators (SPMs), namely lipoxins, resolvins, protectins, and maresins. Herein, biomimetic nanocarriers are produced comprising a cocktail of SPMs‐loaded lipid nanoemulsions (LN) covered with macrophage membranes (Bio‐LN/SPMs). Bio‐LN/SPMs retain on their surface the macrophage receptors involved in cellular interactions and the “marker of self” CD47, which impede their recognition and uptake by other macrophages. The binding of Bio‐LN/SPMs to the surface of endothelial cells (EC) and smooth muscle cells (SMC) is facilitated by the receptors on the macrophage membranes and partly by SPMs receptors. In addition, Bio‐LN/SPMs prove functional by reducing monocyte adhesion and transmigration to/through activated EC and by stimulating macrophage phagocytic activity. After intravenous administration, Bio‐LN/SPMs accumulate in the aorta of ApoE‐deficient mice at the level of atherosclerotic lesions. Also, the safety assessment testing reveals no side effects or immunotoxicity of Bio‐LN/SPMs. Thus, the newly developed Bio‐LN/SPMs represent a reliable targeted nanomedicine for the resolution of inflammation in atherosclerosis.
Single-use duodenoscopes: is performance enough? Time to include sustainability as a prerequisite in clinical practice
Authors: João A. Cunha Neves, Mário Dinis-Ribeiro
Journal: Endoscopy (2023)

Overall, the risk of infection after endoscopic procedures is clinically negligible if proper adherence to disinfection guidelines is ensured [1]. Recently, duodenoscope-associated infections (DAIs) have been referred as a major concern, especially those due to multidrug-resistant organisms (MDROs) [2]. Although duodenoscope-associated MDRO infections are associated with an increased morbimortality, most of them are also avoidable events. In fact, the complex design of duodenoscopes increases bacterial and biofilm harboring, resulting in higher post-procedural infection rates compared with other endoscopes [3]. As a result, this has led to the development of multiple strategies to reduce DAIs, including the improvement of reprocessing and maintenance techniques. However, these measures are far from being perfect and have been demonstrated to be somewhat insufficient [4]. Subsequently, disposable distal end cap attachments and single-use duodenoscopes have emerged as alternative strategies.
Direct diverticular peroral endoscopic myotomy for the treatment of thoracic esophageal diverticula: technique and outcomes
Authors: Julia L. Gauci, Sunil Gupta, Muhammad Abu Arisha, Andrew Tang, Timothy O’Sullivan, Anthony Whitfield, Oliver Cronin, Varan Perananthan, Clarence Kerrison, Eric Y. Lee, Nicholas G. Burgess, Michael J. Bourke
Journal: Endoscopy (2023)

Background Diverticular peroral endoscopic myotomy (POEM) is an alternative to surgery for the management of symptomatic thoracic esophageal diverticula. Conventionally, this requires proximal tunnel formation but a direct approach may simplify the technique. Herein, we report the outcomes of direct diverticular-POEM (DD-POEM). Methods We conducted a single-center prospective observational study evaluating DD-POEM. This involved a direct approach to the diverticulum. Success was defined as an Eckardt score of ≤ 3 without the need for reintervention. Results 10 patients underwent DD-POEM (median age 72 years; interquartile range [IQR] 14.3; male 60 % [n = 6]). Median diverticulum size was 40 mm (IQR 7.5) and median location was 35 cm from the incisors (IQR 8.3). Five patients (50 %) had an underlying dysmotility disorder. The median procedure duration was 60 minutes (IQR 28.8). There were no adverse events. The median hospital stay was 1 day (IQR 0.75). The pre-procedure median Eckardt score of 6 (IQR 4) significantly improved to 0 (IQR 0.75; P &lt; 0.001) at a median follow-up of 14.5 months (IQR 13.8). Success was achieved in all patients. Conclusions DD-POEM was a safe technique for the management of thoracic esophageal diverticula. Owing to its simplicity and excellent performance it should be further evaluated for the treatment of this disorder.